Abstract
In an attempt to understand the signal pathways of opioid µ-receptors for glucose
metabolism, we used loperamide to investigate the glucose uptake into the myoblast
C2C12 cells. Loperamide enhanced the uptake of radioactive deoxyglucose into C2C12 cells in a concentration-dependent manner that was abolished in cells pre-incubated
with naloxone or naloxonazine at concentrations sufficient to block opioid µ-receptors.
Pharmacological inhibition of phospholipase C (PLC) by U73122 resulted in a concentration-dependent
decrease in loperamide-stimulated uptake of radioactive deoxyglucose into C2C12 cells. This inhibition of glucose uptake by U73122 was specific since the inactive
congener, U73343, failed to modify loperamide-stimulated glucose uptake. Moreover,
both chelerythrine and GF 109203X diminished the action of loperamide at concentrations
sufficient to inhibit protein kinase C (PKC). The obtained data suggest that an activation
of opioid µ-receptors in C2C12 cells by loperamide may increase glucose uptake via the PLC-PKC pathway.
Key words
C2C12 cells - Loperamide - Opioid µ-receptors - Phospholipase C - Protein kinase C
References
- 1
Chevlen E.
Opioids: a review.
Current Pain & Headache Reports.
2003;
7
15-23
- 2
Yaksh T L.
Pharmacology and mechanisms of opioid analgesic activity.
Acta anaesthesiol Scand.
1997;
41
94-111
- 3
Smith E M.
Opioid peptides in immune cells.
Advances in Experimental Medicine & Biology.
2003;
521
51-68
- 4
Curry D L, Li C H.
Stimulation of insulin secretion by β-endorphin (1 - 27 and 1 - 31).
Life Sci.
1987;
40
2053-2058
- 5
Locatelli A, Spotti D, Caviezel F.
The regulation of insulin and glucagon secretion by opiates: a study with naloxone
in healthy humans.
Acta Diabetol.
1985;
22
25-31
- 6
Khawaja X Z, Green I C, Thorpe J R, Titheradge M A.
The occurrence and receptor specificity of endogenous opioid peptides with pancreas
and liver of the rat. Comparison with brain.
Biochem J.
1990;
267
233-240
- 7
Cheng J T, Liu I M, Tzeng T F, Tsai C C, Lai T Y.
Plasma glucose lowering effect of β-endorphin in streptozotocin-induced diabetic rats.
Horm Meta Res.
2002;
34
570-576
- 8
Cheng J T, Liu I M, Tzeng T F, Chen W C, Hayakawa S, Yamamoto T.
Release of β-endorphin by caffeic acid to lower plasma glucose in streptozotocin-induced
diabetic rats.
Horm Metab Res.
2003;
35
251-258
- 9
Liu I M, Chi T C, Chen Y C, Lu F H, Cheng J T.
Activation of opioid µ-receptor by loperamide to lower plasma glucose in streptozotocin-induced
diabetic rats.
Neurosci Lett.
1999;
265
183-186
- 10
Tzeng T F, Liu I M, Lai T Y, Tsai C C, Chang W C, Cheng J T.
Loperamide increases glucose utilization in streptozotocin-induced diabetic rats.
Clin Exp Pharmacol Physiol.
2003;
30
734-738
- 11
Sheriff S, Fischer J E, Balasubramaniam A.
Amylin inhibits insulin-stimulated glucose uptake in C2C12 muscle cell line through a cholera-toxin-sensitive mechanism.
Biochim Biophys Acta.
1992;
1136
219-222
- 12
Liu I M, Tsai C C, Lai T Y, Cheng J T.
Stimulatory effect of isoferulic acid on alpha1A-adrenoceptor to increase glucose
uptake into cultured myoblast C2C12 cell of mice.
Auton Neurosci Basic & Clinic.
2001;
88
175-180
- 13
Heel R C, Brogden R N, Speight T M, Avery G S.
Loperamide: a review of its pharmacological properties and therapeutic efficacy in
diarrhea.
Drugs.
1978;
15
33-52
- 14
Crist G H, Xu B, Lanoue F, Lang C H.
Tissue-specific effects of in vivo adenosine receptor blocked on glucose uptake in
Zucker rats.
FASEB J.
1998;
12
1301-1308
- 15
Martin W R.
Opioid antagonists.
Pharmacol Rev.
1967;
19
463-521
- 16
Ling G SF, Simantov R, Clark J A, Pasternak G W.
Naloxonazine actions in vivo.
Eur J Pharmacol.
1986;
129
33-38
- 17
Evans A A, Hughes S, Smith M E.
Delta-opioid peptide receptors in muscles from obese diabetic and normal mice.
Peptides.
1995;
16
361-364
- 18
Ishizuka T, Cooper D R, Hernandez H, Buckley D, Standaert M, Farese R V.
Effects of insulin on diacylglycerol-protein kinase C signaling in rat diaphragm and
soleus muscles and relationship to glucose transport.
Diabetes.
1990;
39
181-190
- 19
Van Epps-Fung M, Gupta K, Hardy R W, Wells A.
A role for phospholipase C activity in GLUT4-Mediated glucose transport.
Endocrinology.
1997;
138
5170-5175
- 20
Wasserman D H, Zinman B.
Exercise in individuals with IDDM.
Diabetes Care.
1994;
17
924-937
- 21
Cheng J T, Liu I M, Chi T C, Tzeng T F, Lu F H, Chang C J.
Plasma glucose lowering effect of tramadol in streptozotocin-induced diabetic rats.
Diabetes.
2001;
50
2815-2821
- 22
Xie W, Samoriski G M, McLaughlin J P, Romoser V A, Smrcka A, Hinkle P M, Bidlack J M,
Gross R A, Jiang H, Wu D.
Genetic alteration of phospholipase C β3 expression modulates behavioral and cellular
responses to mu opioids.
Proc Natl Acad Sci USA.
1999;
96
10 385-10 390
- 23
Smallridge R C, Kiang J G, Gist I D, Fein H G, Gallowat R J.
U-73 122, an aminosteroid phospholipase C antagonist, noncompetitively inhibits thyrotropin-releasing
hormone effects in GH3 rat pituitary cell.
Endocrinology.
1992;
131
1883-1888
- 24
Muto Y, Nagao T, Urushidani T.
The putative phospholipase C inhibitor U73122 and its negative control, U73343, elicit
unexpected effects on the rabbit parietal cell.
J Pharmac Exp Ther.
1997;
282
1379-1388
- 25
Herbert J M, Augereau J M, Gleye J, Maffrand J P.
Chelerythrine is a potent and specific inhibitor of protein kinase C.
Biochem Biophys Res Commun.
1990;
172
993-999
- 26
Toullec D, Pianetti P, Coste H, Bellevergue P, Grand-Perret T, Ajakane M, Baudent V,
Boissin P, Boursier E, Loriolle F, Duhamel L, Charon D, Kirilovsky J.
The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein
kinase C.
J Biol Chem.
266;
1991
15 771-15 781
- 27
Narita M, Ohnishi O, Nemoto M, Aoki T, Suzuki T.
The involvement of phosphoinositide 3-kinase (PI3-Kinase) and phospholipase C gamma
(PLC gamma) pathway in the morphine-induced supraspinal antinociception in the mouse.
Nihon Shinkei Seishin Yakurigaku Zasshi.
2001;
21
7-14
- 28
Freye E, Latasch L.
Development of opioid tolerance - molecular mechanisms and clinical consequences.
Anasthesiol Intensivmed Notfallmed Schmerzther.
2003;
38
14-26
- 29
Neri L M, Borgatti P, Capitani S, Martelli A M.
Protein kinase C isoforms and lipid second messengers: a critical nuclear partnership?.
Histol Histopath.
2002;
17
1311-1316
- 30
Bandyopadhyay G, Standaert M L, Kikkawa U, Ono Y, Moscat J, Farese R V.
Effects of transiently expressed atypical (zeta, lambda), conventional (alpha, beta)
and novel (delta, epsilon) protein kinase C isoforms on insulin-stimulated translocation
of epitope-tagged GLUT4 glucose transporters in rat adipocytes: specific interchangeable
effects of protein kinases C-zeta and C-lambda.
Biochem J.
1999;
337
461-370
Prof. J.-T. Cheng
Department of Pharmacology · College of Medicine · National Cheng Kung University
Tainan City · Taiwan 70101 · R.O.C.
Telefon: +886(6)2372706
Fax: +886(6)2386548 ·
eMail: jtcheng@mail.ncku.edu.tw